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GRASPA (Erythrocytes Encapsulating L-asparaginase) in Patients With Relapse of Acute Lymphoblastic Leukemia (GRASPIVOTALL)

Primary Purpose

Acute Lymphoblastic Leukemia, in Relapse

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
GRASPA
L-asparaginase
Sponsored by
ERYtech Pharma
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Lymphoblastic Leukemia, in Relapse focused on measuring acute lymphoblastic leukemia, relapse, asparaginase

Eligibility Criteria

1 Year - 55 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patient from 1 to 55 years old (Children and adolescents from 1 to 17 years/ Adults from 18 to 55 years)
  • Patients with 1st ALL relapse, which could be either isolated bone marrow relapse, or combined (medullary and extra-medullary) relapse, or extra-medullary isolated relapse; or lymphoblastic lymphoma (excepted Burkitt lymphoma) OR Failure to ALL first line treatment (no complete remission obtained)
  • Patient previously treated with free E.Coli L-asparaginase form or pegylated one
  • Performance Status ≤ 2 (WHO score)
  • Patient informed and consent provided (the 2 parents need to consent when children are below 18)

Exclusion Criteria:

  • ALL t(9;22) and/or BCR-ABL positive (Philadelphia chromosome positive)
  • Patient with 2nd relapse and over
  • Women of childbearing potential without effective contraception as well as pregnant or breast feeding women
  • Patient unable to receive treatments used in global chemotherapy protocols, due to general or visceral conditions such as:Severe cardiac impairment (NYHA grade 3 or 4 cardiomyopathy)/Serum creatinine 2 x ULN unless related to ALL /ALT or AST 5 x ULN unless related to ALL /Pancreatitis history /Other malignancy that ALL / Severe Infection, HIV positive, active hepatitis related to B or C virus infection / Trisomy 21 / Other serious conditions according to investigator's opinion
  • Known grade 4 allergic reaction to E.Coli L-asparaginase (according NCI-CTCAE, Version 3.0)
  • History of grade 3 transfusional incident
  • Presence of specific anti-erythrocyte antibodies preventing from getting a compatible erythrocyte concentrate for the patient
  • Patient under concomitant treatment likely to cause hemolysis
  • Patient undergoing yellow fever vaccination
  • Patient under phenytoin treatment
  • Patient included in previous clinical study less than 6 weeks ago

Sites / Locations

  • Hopital Des Enfants Reine Fabiola
  • Chr de La Citadelle
  • Chu D'Angers
  • Hopital Saint Jacques
  • Hopital Pellegrin Enfants
  • Chu Estaing
  • Hopital Henri Mondor
  • Chu Grenoble
  • Chru Lille - Hop Jeanne de Flandres
  • Institut Hematologie Oncologie Pediatrique
  • Institut Paoli Calmettes
  • Hopital Mere Enfant
  • Hotel Dieu
  • Hopital de L'Archet 2
  • Hopital Armand Trousseau
  • Hopital Robert Debre
  • Hopital Saint Louis
  • Hopital Haut-Leveque
  • Hopital Lyon Sud
  • Chru Hopital Sud
  • Centre Henri Becquerel
  • Chu Hopital Nord
  • Institut Cancerologie de La Loire
  • Hopital de Hautepierre
  • Chu de Toulouse Enfants
  • Hotel Dieu
  • Hopital Brabois Enfants
  • Hopital de Brabois

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

GRASPA

reference L-asparaginase

Arm Description

Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles)

For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL). •for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks). NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity) •for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles).

Outcomes

Primary Outcome Measures

Duration of Asparaginase Activity >100 U/L During Induction
Co-primary efficacy endpoint: duration in days of asparaginase activity >100 U/L in whole blood during the induction treatment phase: last available date/time of activity >100 UI/L before activity drops below 100 U/L - date/time of first activity >100 UI/L. Asparaginase activity is compared for GRASPA versus native ASNase to demonstrate the non-inferiority of GRASPA.
Allergic Reaction During Induction Phase
Co-primary safety endpoint: allergic reaction regardless of grade during induction phase. Only those reactions that were reported in relation to the treatment to which the patient was randomised were counted.

Secondary Outcome Measures

Complete Remission (CR)
CR is defined as, no physical evidence of leukemia, normal CBC, cytologic remission: normally regenerating bone marrow, with <5% leukemic blasts and the absence of detectable CNS or extramedullary disease, evaluated with physical examination and CSF findings, at the end of induction
Overall Survival (OS)
OS is defined as the time from randomisation or date of inclusion (allergic arm) until death due to any cause. Patients who did not die were censored at 36 months of follow-up or the date of the patient's last visit, whichever was earlier.
Event Free Survival
EFS is defined as the time from randomisation until the first documented sign of disease relapse or death due to any cause. In line with CHMP guidance (CHMP, 2016), patients who did not achieve CR at the end of the induction period were considered to have had an event at time 0. For the patients enrolled in the GRASPA allergic arm, EFS is defined from the date of inclusion in the study. Patients who achieved CR at the end of induction and who did not have a documented relapse or death due to any cause were censored at 36 months of follow-up or the date of the patient's last visit, whichever was earlier.

Full Information

First Posted
January 10, 2012
Last Updated
February 1, 2022
Sponsor
ERYtech Pharma
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1. Study Identification

Unique Protocol Identification Number
NCT01518517
Brief Title
GRASPA (Erythrocytes Encapsulating L-asparaginase) in Patients With Relapse of Acute Lymphoblastic Leukemia
Acronym
GRASPIVOTALL
Official Title
Phase 2/3 Study Evaluating Efficacy and Safety of Erythrocytes Encapsulating L-asparaginase (GRASPA)Versus Reference L-asparaginase Treatment in Combination With Standard Polychemotherapy in Patient With First Recurrence of Philadelphia Negative Acute Lymphoblastic Leukemia
Study Type
Interventional

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Completed
Study Start Date
December 2009 (Actual)
Primary Completion Date
September 2014 (Actual)
Study Completion Date
October 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
ERYtech Pharma

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Asparaginase is a cornerstone in the treatment of ALL, but its utility is limited by toxicities including hypersensitivity. Clinical allergy is associated with inactivation of asparaginase by antibodies (A-Abs), which can also neutralize asparaginase without any clinical signs of hypersensitivity (silent inactivation). GRASPA improves pharmacokinetics, tolerability and maintain circulating asparaginase activity due to the protective barrier of the erythrocyte membrane. This study is run to confirm the benefit/risk profile of GRASPA at 150 IU/kg in combination with the COOPRALL regimen in adults and children patients with relapsed ALL, with or without known hypersensitivity to L-asparaginase.
Detailed Description
This open, randomized international Phase 2/3 study will enrol patients with relapsed ALL. The co-primary endpoints were the duration of asparagine depletion < 2µmol/L and the incidence of asparaginase hypersensitivity during induction. Key secondary endpoints are complete remission (CR), minimal residual disease (MRD), event free survival (EFS) and overall survival (OS).The study was powered to detect 3-fold difference in the incidence of allergic reactions between treatments. patients will be randomized to GRASPA or to Reference L-asparaginase. Patients with history of hypersensitivity to previous L-asparaginase treatment will be treated with GRASPA (exploratory arm)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Lymphoblastic Leukemia, in Relapse
Keywords
acute lymphoblastic leukemia, relapse, asparaginase

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
85 (Actual)

8. Arms, Groups, and Interventions

Arm Title
GRASPA
Arm Type
Experimental
Arm Description
Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles)
Arm Title
reference L-asparaginase
Arm Type
Active Comparator
Arm Description
For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL). •for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks). NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity) •for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles).
Intervention Type
Drug
Intervention Name(s)
GRASPA
Other Intervention Name(s)
ERY001
Intervention Description
one injection of GRASPA 150 IU/kg at each cycle of chemotherapy
Intervention Type
Drug
Intervention Name(s)
L-asparaginase
Other Intervention Name(s)
KIDROLASE
Intervention Description
3 to 4 Injections of Native E.coli asparaginase 10000IU/m² (every 3 days) at each cycle of chemotherapy
Primary Outcome Measure Information:
Title
Duration of Asparaginase Activity >100 U/L During Induction
Description
Co-primary efficacy endpoint: duration in days of asparaginase activity >100 U/L in whole blood during the induction treatment phase: last available date/time of activity >100 UI/L before activity drops below 100 U/L - date/time of first activity >100 UI/L. Asparaginase activity is compared for GRASPA versus native ASNase to demonstrate the non-inferiority of GRASPA.
Time Frame
Induction treatment period (i.e. 28 days)
Title
Allergic Reaction During Induction Phase
Description
Co-primary safety endpoint: allergic reaction regardless of grade during induction phase. Only those reactions that were reported in relation to the treatment to which the patient was randomised were counted.
Time Frame
Induction treatment period (i.e. 28 days)
Secondary Outcome Measure Information:
Title
Complete Remission (CR)
Description
CR is defined as, no physical evidence of leukemia, normal CBC, cytologic remission: normally regenerating bone marrow, with <5% leukemic blasts and the absence of detectable CNS or extramedullary disease, evaluated with physical examination and CSF findings, at the end of induction
Time Frame
Induction treatment period (i.e. 28 days)
Title
Overall Survival (OS)
Description
OS is defined as the time from randomisation or date of inclusion (allergic arm) until death due to any cause. Patients who did not die were censored at 36 months of follow-up or the date of the patient's last visit, whichever was earlier.
Time Frame
Overall trial period to 36 months
Title
Event Free Survival
Description
EFS is defined as the time from randomisation until the first documented sign of disease relapse or death due to any cause. In line with CHMP guidance (CHMP, 2016), patients who did not achieve CR at the end of the induction period were considered to have had an event at time 0. For the patients enrolled in the GRASPA allergic arm, EFS is defined from the date of inclusion in the study. Patients who achieved CR at the end of induction and who did not have a documented relapse or death due to any cause were censored at 36 months of follow-up or the date of the patient's last visit, whichever was earlier.
Time Frame
Overall trial period to 36 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patient from 1 to 55 years old (Children and adolescents from 1 to 17 years/ Adults from 18 to 55 years) Patients with 1st ALL relapse, which could be either isolated bone marrow relapse, or combined (medullary and extra-medullary) relapse, or extra-medullary isolated relapse; or lymphoblastic lymphoma (excepted Burkitt lymphoma) OR Failure to ALL first line treatment (no complete remission obtained) Patient previously treated with free E.Coli L-asparaginase form or pegylated one Performance Status ≤ 2 (WHO score) Patient informed and consent provided (the 2 parents need to consent when children are below 18) Exclusion Criteria: ALL t(9;22) and/or BCR-ABL positive (Philadelphia chromosome positive) Patient with 2nd relapse and over Women of childbearing potential without effective contraception as well as pregnant or breast feeding women Patient unable to receive treatments used in global chemotherapy protocols, due to general or visceral conditions such as:Severe cardiac impairment (NYHA grade 3 or 4 cardiomyopathy)/Serum creatinine 2 x ULN unless related to ALL /ALT or AST 5 x ULN unless related to ALL /Pancreatitis history /Other malignancy that ALL / Severe Infection, HIV positive, active hepatitis related to B or C virus infection / Trisomy 21 / Other serious conditions according to investigator's opinion Known grade 4 allergic reaction to E.Coli L-asparaginase (according NCI-CTCAE, Version 3.0) History of grade 3 transfusional incident Presence of specific anti-erythrocyte antibodies preventing from getting a compatible erythrocyte concentrate for the patient Patient under concomitant treatment likely to cause hemolysis Patient undergoing yellow fever vaccination Patient under phenytoin treatment Patient included in previous clinical study less than 6 weeks ago
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yves Bertand, MD
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hopital Des Enfants Reine Fabiola
City
Bruxelles
Country
Belgium
Facility Name
Chr de La Citadelle
City
Liege
Country
Belgium
Facility Name
Chu D'Angers
City
Angers
Country
France
Facility Name
Hopital Saint Jacques
City
Besancon
Country
France
Facility Name
Hopital Pellegrin Enfants
City
Bordeaux
Country
France
Facility Name
Chu Estaing
City
Clermont Ferrand
Country
France
Facility Name
Hopital Henri Mondor
City
Creteil
Country
France
Facility Name
Chu Grenoble
City
Grenoble
Country
France
Facility Name
Chru Lille - Hop Jeanne de Flandres
City
Lille
Country
France
Facility Name
Institut Hematologie Oncologie Pediatrique
City
Lyon
Country
France
Facility Name
Institut Paoli Calmettes
City
Marseille
Country
France
Facility Name
Hopital Mere Enfant
City
Nantes
Country
France
Facility Name
Hotel Dieu
City
Nantes
Country
France
Facility Name
Hopital de L'Archet 2
City
Nice
Country
France
Facility Name
Hopital Armand Trousseau
City
Paris
Country
France
Facility Name
Hopital Robert Debre
City
Paris
Country
France
Facility Name
Hopital Saint Louis
City
Paris
Country
France
Facility Name
Hopital Haut-Leveque
City
Pessac
Country
France
Facility Name
Hopital Lyon Sud
City
Pierre Benite
Country
France
Facility Name
Chru Hopital Sud
City
Rennes
Country
France
Facility Name
Centre Henri Becquerel
City
Rouen
Country
France
Facility Name
Chu Hopital Nord
City
Saint Etienne
Country
France
Facility Name
Institut Cancerologie de La Loire
City
Saint Priest En Jarez
Country
France
Facility Name
Hopital de Hautepierre
City
Strasbourg
Country
France
Facility Name
Chu de Toulouse Enfants
City
Toulouse
Country
France
Facility Name
Hotel Dieu
City
Valenciennes
Country
France
Facility Name
Hopital Brabois Enfants
City
Vandoeuvre Les Nancy
Country
France
Facility Name
Hopital de Brabois
City
Vandoeuvre Les Nancy
Country
France

12. IPD Sharing Statement

Plan to Share IPD
No

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GRASPA (Erythrocytes Encapsulating L-asparaginase) in Patients With Relapse of Acute Lymphoblastic Leukemia

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